Two general classes of organic pharmaceuticals useful in the treatment of the mental disease depression in humans have been recognized: (1) tricyclic antidepressants, as exemplified by amitriptyline and protriptylene, and (2) monoamine oxidase inhibitors (MAOI), as exemplified by the commercially available drugs Nardil, Parnate, and L-deprenyl.
Both types of drugs are generally regarded as effective, but both have undesirable side effects. For tricyclic drugs, recognized side effects include dry mouth, orthostatic hypotension, and impotence, and these effects are frequent. The most significant side effect of the MAOI drugs is a rare but serious one: sudden and dangerous life-threatening elevation of blood pressure when the patent taking such drugs also consumes foods high in the naturally occurring substance tyramine. Cheese is the most common food containing large amounts of tyramine, so that this side effect is often known colloquially in the medical profession as the "cheese effect".
Because the cheese effect can cause very serious medical problems, including death in severe cases, MAOI drugs are little used, even though they are generally free from the other more common side effects of the tricyclic drugs and are believed to have at least equal effectiveness in the treatment of most types of depression.
Tyramine is known to be capable of causing severe hypertension when presented in the blood, but it is normally converted in the gastrointestinal tract by the action of a monoamine oxidase enzyme naturally present there, to other substances incapable of causing dangerous hypertension. When a patient is taking an MAOI orally, however, deactiviation of the tyramine by gastrointestinal enzymes is at least partially repressed, and serious clinical symptons may result.
Recent research has recognized a distinction among the MAOI drugs themselves, connected with recognition of the existence of two isozymes of monoamine oxidase itself, denoted simply as the A and B isozymes. Nardil and Parnate are recognized as primarily inhibitors of the action of monoamine oxidase A, while deprenyl first inhibits the action of monoamine oxidase B and significantly inhibits the action of monoamine oxidase A only at larger doses. The tyramine deactivating monoamine oxidase enzyme is primarily type A, so that it would appear that administration of L-deprenyl should not induce the cheese effect. The cheese effect, however, is potentially so serious that, the use of L-deprenyl in an oral dosage is nevertheless counterindicated simply because it does appear to have some MAO-A inhibiting activity. On the other hand, the monoamine oxidases in the brain are primarily of the B type, so that LDY is very effective in inhibiting their action.
There are three general modes of administration which have been used for the antidepressants under consideration, which must reach the blood stream in the course of exerting their therapeutic effects: oral, intravascular, and transdermal. Because of the danger of infection and the need for trained personnel for administration, intravascular administration is disfavored when one of the other two means is effective. Drugs for treating depression have traditionally been administered orally, but transdermal administration of some of the tricyclic antidepressant drugs, and by implication, any suitable drug, has also been taught by U.S. Pat. No. 4,230,105 of Oct. 28, 1980 to Harwood. Transdermal administration of drugs in general has been taught by earlier patents, including some cited in the Harwood reference.
One highly restrictive limitation on the transdermal administration of drugs is the possibility of skin irritation or allergic reactions induced by such administration. This is particularly important when considering treatment of depression since MAO inhibitors are required to be used at higher dose levels.
In Whatever dosage form it may be administered, an antidepressant drug must be constantly present in the body for up to six months if the patient is to derive maximum benefit and not revert to a depressed state.
If transdermal administration of an antidepressant is to be used, this means very prolonged and constant or near-constant contact between the patient's skin and the pharmaceutical including the drug. It is well known that long-term exposure of skin to a chemical substance even at low dosages often will result either in a local skin inflammation at the side of contact or a more general immunologically based allergic reaction that can have a serious adverse effect on the entire body. When either of these events occur, the affected patient should immediately discontinue contact with the offending agent. Since MAO inhibitors generally were found heretofore to be skin irritants, clearly their use for antidepression treatment by transdermal techniques was not indicated.